Gout is one of the oldest documented human illnesses. It develops when sharp crystals form inside joints, triggering intense swelling and pain, and is considered a type of arthritis. Researchers at Georgia State University believe they may have uncovered a surprisingly ancient way to address it.
A study in Scientific Reports describes how scientists used CRISPR gene-editing tools to restore a gene that disappeared from the human lineage millions of years ago. Bringing this gene back lowered uric acid, the substance responsible for gout and several other health problems.
The long-lost component is uricase, an enzyme that most other animals continue to carry.
Uricase breaks down uric acid, a waste product that routinely forms in the blood. If uric acid levels rise too much, it can crystallize in the joints and kidneys, causing gout, kidney disease and a number of related conditions.
Why Humans Lost Uricase
Humans and other apes shed the uricase gene roughly 20 to 29 million years in the past. Some experts argue this change may have once offered an advantage. According to research cited in Seminars in Nephrology, scientists including Dr. Richard Johnson of the University of Colorado have suggested that elevated uric acid helped early primates convert fruit sugars into fat, providing a survival boost during lean times.
Today, however, that ancient adaptation contributes to a range of modern metabolic issues. This is the challenge that Georgia State biology professor Eric Gaucher and his team aimed to test.
"Without uricase, humans are left vulnerable," said Gaucher, a co-author of the study. "We wanted to see what would happen if we reactivated the broken gene."
Reintroducing an Ancient Gene With CRISPR
Working with postdoctoral researcher Lais de Lima Balico, Gaucher relied on CRISPR-Cas9, often referred to as molecular scissors, to insert a reconstructed version of the ancient uricase gene into human liver cells. This allowed the team to observe how the enzyme functioned in a modern biological environment.
The results surprised them. Uric acid levels fell sharply, and liver cells no longer accumulated fat when exposed to fructose. Because experiments in individual cells cannot always predict what will occur in more complex systems, the researchers advanced to a more sophisticated model.
They tested the gene in 3D liver spheroids, which are small, lab-grown structures that more closely resemble actual organ function. The reintroduced uricase gene again reduced uric acid. The enzyme also moved into peroxisomes, the cellular compartments where uricase naturally operates, suggesting the therapy might behave safely and appropriately in living organisms.
"By reactivating uricase in human liver cells, we lowered uric acid and stopped the cells from turning excess fructose into triglycerides -- the fats that build up in the liver," Gaucher said.
The Wider Impact of High Uric Acid
The findings extend well beyond gout. High uric acid, known as hyperuricemia, is associated with many modern health disorders. Research highlighted in the journal Hypertension has linked elevated uric acid to hypertension and cardiovascular disease, and the risks have been compared to those of high cholesterol.
These concerns are reflected in patient statistics. Between one-quarter and one-half of people with high blood pressure also have high uric acid, and in newly diagnosed hypertension, that overlap rises to 90 percent, according to the study.
"Hyperuricemia is a dangerous condition," Gaucher said. "By lowering uric acid, we could potentially prevent multiple diseases at once."
Toward Future Therapies
Current treatments for gout are not effective for everyone, and some individuals experience adverse reactions to existing uricase-based medications. A CRISPR method that restores uricase directly in liver cells could avoid these issues.
"Our genome-editing approach could allow patients to live gout-free lives and potentially prevent fatty liver disease," Gaucher said.
Animal studies are the next step, followed by human trials if early results hold up. Potential delivery methods include direct injections, returning modified liver cells to patients, or using lipid nanoparticles (the same technology employed in some COVID-19 vaccines).
If the strategy proves safe, Gaucher believes it could reshape the way gout and related metabolic disorders are treated. However, several challenges still need to be addressed.
"Genome-editing still faces substantial safety concerns," he said. "Once those are addressed, society will be faced with contentious ethical discussions about who should and should not have access."